Advanced glycation end products are associated with pulse pressure in type 1 diabetes: the EURODIAB Prospective Complications Study

We investigated the associations of pulse pressure (a measure of arterial stiffness) with the early glycation products hemoglobin A1c (HbA1c) and Amadori albumin and the advanced glycation end products pentosidine, Nepsilon-(carboxymethyl)lysine and Nepsilon-(carboxyethyl)lysine in a large group of type 1 diabetic individuals of the EURODIAB Prospective Complications Study. We did a cross-sectional nested case-control study from the EURODIAB Prospective Complications Study of 543 (278 men) European individuals with type 1 diabetes diagnosed at <36 years of age. We used linear regression analyses to investigate the association of pulse pressure with glycation products. Pulse pressure was significantly associated with plasma levels of Nepsilon-(carboxymethyl)lysine and Nepsilon-(carboxyethyl)lysine but not with HbA1c, Amadori albumin, and urinary levels of pentosidine. Regression coefficients adjusted for age, sex, mean arterial pressure, and duration of diabetes were 0.09 mm Hg (P=0.003) per 1 microM/M lysine Nepsilon-(carboxymethyl)lysine; 0.24 mm Hg (P=0.001) and -0.03 mm Hg (P=0.62) per 1 microM/M lysine Nepsilon-(carboxyethyl)lysine (in individuals with and without complications, respectively; P interaction=0.002); and 0.50 mm Hg (P=0.16) per 1% HbA1c; 0.07 mm Hg (P=0.12) per 1 U/mL Amadori albumin; and 0.77 mm Hg (P=0.48) per 1 nmol/mmol creatinine pentosidine. In young type 1 diabetic individuals, arterial stiffness is strongly associated with the advanced glycation end products Nepsilon-(carboxymethyl)lysine and Nepsilon-(carboxyethyl)lysine. These findings suggest that the formation of advanced glycation end products is an important pathway in the development of arterial stiffness in young type 1 diabetic individuals

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Shear strength of the Bremanger Sandstone: “Determining the basic friction angle using a Golder Direct Shear Box”

This project focuses on the shear strength of Devonian sandstone cobbles that will protect the area between the sea-water breaker and the beach and will be used to construct a runway for a large crane for the new Maasvlakte 2. In rock slope design the shear strength of sliding interfaces is often based on Coulomb’s model in which shear strength (?) is expressed as a function of cohesion (c), normal load (?) and the friction angle (?). A specific model on shear strength behaviour of rockfill is proposed by Barton (Barton, 2008). Barton’s model can be used to predict shear strength of rock joints and rock fill when basic rock properties are known. One main factor of influence on shear strength of rockjoints and rock fill is the basic friction angle. A Golder direct shear box was used to obtain the basic friction angle of the Bremanger sandstone. First the basic friction angle was determined (using flat saw-cut surfaces). In the next phase fresh tensile cracked rock discontinuities were tested. Measured stresses were corrected using measured dilatancy to estimate the basic friction angle. The influence of different rock properties such as roughness, rock strength and visible layering was studied. Finally natural non-matching surfaces were researched to see how the shear strength changes due to the weathering and smoothening of the rock. The following main results and conclusions were drawn from the research project: Flat saw-cut surfaces: - The basic friction angle of the Bremanger (flat saw-cut surfaces) was not measured correctly. Since the sample halves were polished in order to make them match, the measured friction angle is rather an indication of the polishing process than the rock properties. Tensile-cracked surfaces: - For the tensile cracked samples, the average residual friction angle is 1111 degrees. The residual friction angle was used as the basic friction angle rather than the peak friction angle since high peak shear stress values are caused by asperities at the edges of the tested samples. The shear strength dropped massively as soon as these asperities broke off. - Residual friction angles do not depend on wet or dry test conditions. - There is a direct link between UCS and shear strength. The higher the UCS value, the higher the residual stress value. - The Bremanger sandstone is a Metasandstone. Layering is still macroscopically visible but cleavage does not occur along this layering. Natural non-matching surfaces: - These surfaces were weathered and smoothened. This caused the residual friction angle to drop to 1111degrees. 3D Leica pictures confirmed that the surface of this tested sample was smoother than the fresh tensile-cracked ones.Geo-EngineeringGeotechnologyCivil Engineering and Geoscience

Cut-off Grade Based Sublevel Stope Mine Optimization: Introduction and evaluation of an optimization approach and method for grade risk quantification

The aim of this research project was to introduce and evaluate an optimization approach for sublevel stope mine optimization using the AMIRA Stope Optimizer that includes grade-risk quantification and can be used by Boliden engineers for future mine planning and economic assesment. It has long been realized that mining simply every part of an orebody with a grade higher than 0 is not economical and will not lead to a successful mining operation. By selecting a cut-off grade it is decided what part of an orebody is economical to extract. In its most basic form the cut-off grade is a break-even grade which makes sure that each block of ore pays for its own mining, processing and refining cost resulting in zero gains and losses for a tonne of ore containing this grade (zero profit). As the aim of most mining companies is to maximize the Net Present Value of its mining projects it becomes clear that the break-even grade in many cases does not accomplish this goal. Research in the field of cut-off grade optimization has proven that a relationship exists between the selection of a cut-off grade and project NPV. Although mathematical equations exist to optimize the cut-off grade and prioject NPV, they contain several simplifications of reality. The mathematical equations are therefore difficult to apply in real world problems and as a result the underground mine planning process is still a mainly manual time consuming process. Boliden Mineral AB (Boliden) is a Swedish mining company that invested in the development of the AMIRA Stope Optimizer. The stope optimization software assists in the optimization of underground stopes at user defined cut-off grades and was developed to accelerate the time consuming underground optimization process. The AMIRA Stope Optimizer was evaluated to define its capabilities and limitations and it was concluded that the software is very valuable in strategic mine planning studies. The stope optimization software was implemented in the mine optimzation process and succesfully applied to optimize a project strategy for one of Boliden’s mineral deposits (Älgträsk). It was found that the optimum gold cut-off grade for this deposit is 1.8 g/t, resulting in a project NPV of 31MSEK. This is a 35% increase in project NPV compared to the break-even grade of 1.6 g/t. The spatial grade uncertainty was identified as a major risk in underground stope design and therefore the optimization process was further extended to account for grade risk in mineral resources and subsequent stope optimization. Grade risk can be assessed by comparing estimated block models of a mineral resource (e.g. Kriging) with stochastic simulated block models of the same mineral resource. Because the simulations provide equally true, but different, interpretations of the mineral resource it is possible to quantify grade risk involved in Kriging estimation model based optimized mine designs. The optimization process was adapted to account for grade risk early in the design process. Instead of optimizing the mining project at a certain cut-off grade based on the estimated model only and subsequently back-analyze the optimization outcome using the simulations, the simulated block models are used in the optimization process itself. By the application of a target confidence level to the desired cut-off grade, the underground production areas are designed to meet the cut-off grade in the estimated model, as well as a percentage of the simulated models. This will reduce the risk of a stope not meeting the cut-off grade which would result in a loss of money. By optimizing the mining project at different confidence levels (eg. 20%, 40%, 60%, 80%) the project economic risk can be quantified and used in decision making.Resource EngineeringGeoscience & EngineeringCivil Engineering and Geoscience

Variant location is a novel risk factor for individuals with arrhythmogenic cardiomyopathy due to a desmoplakin (DSP) truncating variant

Background:Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. Methods:Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. Results:There were 98 probands and 72 family members (mean age at diagnosis 43 +/- 8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). Conclusions:In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.Cardiolog